Bone marrow stromal cells attenuate sepsis via prostaglandin E2–dependent reprogramming of host macrophages to increase their interleukin-10 production

Ne´meth, K. et al., Nat. Med. 15, 42-49 (2009)

Speaker: 阮馨怡                           Time: 13:10~14:10, Mar. 11, 2009

Commentator: 凌斌 老師            Place: Room 601

Abstract:

      Sepsis is a complicated clinical syndrome with generally activation of inflammation and coagulation systems. Infection, trauma, ischemia, and severe injury contribute to the pathogenesis of severe sepsis¹. Dysregulation of the inflammation and coagulation systems leads to progressive multiple organ failures, septic shock, and death. Previous studies have shown that bone marrow stromal cells (BMSCs) are potent modulators² and have immunosuppressive effects on immune responses. Cecal ligation and puncture (CLP), an animal model of sepsis, mimics human peritonitis, which has been used for more than two decades. In this study, the authors demonstrated that the intravenous injection of BMSCs could respond to the presence of infectious agents and modulate the response of the host immune system by increasing prostaglandin E2 synthesis, and that subsequent activation of prostaglandin E2 and E4 receptors on the macrophages resulted in the release of IL-10³, an anti-inflammatory cytokine. The monocyte- and macrophage-derived IL-10 appeared to decrease plasma pro-inflammatory cytokine concentrations and prevent neutrophils from migrating into tissues and causing oxidative damage, thus mitigating multiorgan damage. Furthermore, high circulating neutrophil counts in the BMSC-treated mice could help reduce blood bacteria. In conclusion, BMSCs treatment could beneficially modulate the response of the host immune system due to interacting with circulating and tissue monocytes and macrophages and reprogramming them, thus enabling precise control of the inflammatory response.

References:

1. Ulloa, L. & Tracey, K.J. 2005. The ‘‘cytokine profile’’: a code for sepsis. Trends Mol. Med.11, 56–63.

2. Le Blanc, K. et al. 2004. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 363, 1439–1441.

3. Kubo, S. et al. 2004. E-prostanoid (EP)2/EP4 receptor-dependent maturation of human monocyte-derived dendritic cells and induction of helper T2 polarization. J. Pharmacol. Exp. Ther. 309, 1213–1220.